Prof John Silke, Division Head | WEHI Researcher Profile

Q: The use of IAP antagonists to treat cancer

We are taking several approaches to explore the best way that IAP antagonists can be used in the clinic to treat cancer. This is an area of intense research world-wide but we have unique advantages including:* Access to amazing patient-derived xenograft resources.* A longstanding collaboration with TetraLogic Pharamceuticals Corporation which is developing birinapant, an IAP-antagonist, in clinical trials.* The institute’s high throughput screening facility.Using these reagents we are looking for the cancer types most responsive to birinapant killing and novel drug combinations that can overcome the resistance of other cancer types.

Q: Can inhibition of necroptosis limit or reduce inflammatory diseases?

Using laboratory models of psoriasis and systemic inflammation we have shown that genetic loss of the key necroptosis effectors RIPK3 and MLKL significantly attenuates many aspects of the disease.Working with other divisions at the institute, we have discovered novel small molecular inhibitors of necroptosis which we are now testing in this and other disease models.

Q: What role do IAPs and RIPK kinases play in generating an inflammatory response?

We have shown that IAPs and RIPK2 play an important role in regulating signalling from NOD receptors, essential intracellular receptors that detect and respond to bacterial products. We are exploring a small molecule approach to explore this pathway and with collaborators at the institute we have developed and characterised a new RIPK2 inhibitor.This has a fascinating mode of action: it delays signalling events such as NF-κB activation by only an hour or less, but completely inhibits the production of inflammatory cytokines by this pathway. We are exploring this further with mass spectrometry approaches.

Q: How does the master regulator of inflammation, TNF, perform its role?

cIAPs and RIPK1 play important roles in regulating the signalling outcome downstream of TNF/TNFR1 activation. We have a long-standing interest in understanding how they function in this role, using a combination of genetics, small molecule inhibitor and mass spectrometry approaches.More recently we have expanded our purview of this fascinating signalling paradigm by exploring the role of other regulators of this pathway including the linear ubiquitin assembly complex comprising the proteins SHARPIN, HOIL-1 and HOIP.

About

My lab is interested in how cell death and inflammation are regulated. We focus on three key families of molecules:

* The tumor necrosis factor super family (TNFSF) that regulates the immune system and inflammation.
* Ubiquitin E3 ligases that play an important role regulating signalling from the TNFSF and other critical immune regulators.
* RIP Kinases, which play an important role in effecting inflammation, apoptotic and necroptotic cell death.

My lab uses a wide array of approaches including biochemistry, cell biology, small molecules and genetics so that discoveries made at the molecular level can be transposed into physiological findings in vivo. Using this approach I hope we can make medically relevant discoveries that can be translated into human treatments.

Education

Grants and funding

Publications

Selected publications from Prof John Silke

Wang XS, Jiou J, Cerra A, Cobbold SA, Jochem M, Mak KHT, Corcilius L, Silke J, Payne RJ, Goddard-Borger ED, Komander D, Lechtenberg BC. The RBR E3 ubiquitin ligase HOIL-1 can ubiquitinate diverse non-protein substrates in vitro. Life Science Alliance. 2025;8(6):10.26508/lsa.202503243

Liu L, Silke J. AXIN2 is a non‐redundant regulator of AXIN1 stability and β‐catenin in colorectal cancer cells. The FEBS Journal. 2025;292(5):10.1111/febs.17336

Ramani RS, Tan I, Bussau L, O’Reilly LA, Silke J, Angel C, Celentano A, Whitehead L, McCullough M, Yap T. Convolutional neural networks for accurate real-time diagnosis of oral epithelial dysplasia and oral squamous cell carcinoma using high-resolution in vivo confocal microscopy. Scientific Reports. 2025;15(1):10.1038/s41598-025-86400-5

Lelliott EJ, Naddaf J, Ganio K, Michie J, Wang S, Liu L, Silke N, Ahn A, Ramsbottom KM, Brennan AJ, Freeman AJ, Goel S, Vervoort SJ, Kearney CJ, Beavis PA, McDevitt CA, Silke J, Oliaro J. Intracellular zinc protects tumours from T cell-mediated cytotoxicity. Cell Death & Differentiation. 2024;31(12):10.1038/s41418-024-01369-4

Anderton H, Bandala-Sanchez E, Simpson DS, Rickard JA, Ng AP, Di Rago L, Hall C, Vince JE, Silke J, Liccardi G, Feltham R. Correction to: RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development. Cell Death & Differentiation. 2024;31(12):10.1038/s41418-024-01401-7

Nordmann TM, Anderton H, Hasegawa A, Schweizer L, Zhang P, Stadler P-C, Sinha A, Metousis A, Rosenberger FA, Zwiebel M, Satoh TK, Anzengruber F, Strauss MT, Tanzer MC, Saito Y, Gong T, Thielert M, Kimura H, Silke N, Rodriguez EH, Restivo G, Nguyen HH, Gross A, Feldmeyer L, Joerg L, Levesque MP, Murray PJ, Ingen-Housz-Oro S, Mund A, Abe R, Silke J, Ji C, French LE, Mann M. Spatial proteomics identifies JAKi as treatment for a lethal skin disease. Nature. 2024;635(8040):10.1038/s41586-024-08061-0

Wang Y, Liu Z, Si Q, Lu W, Song Y, Jin W, Yang X, Li Z, Hu X, Ding L, Jing Y, Weng P, Yu Q, O’Reilly LA, Silke J, Zhang X, Hu Q, Ni Y. Complex IIa formation and ABC transporters determine sensitivity of OSCC to Smac mimetics. Cell Death & Disease. 2024;15(11):10.1038/s41419-024-07253-w

Nordmann T, Anderton H, Hasegawa A, Schweizer L, Zhang P, Stadler P, Sinha A, Andreas M, Florian R, Maximilian Z, Satoh TK, Saito Y, Gong T, Thielert M, Kimura H, Nguyen H, Levesque M, Murray P, Ingen-Housz-Oro S, Mund A, Abe R, Silke J, Ji C, French LE, Mann M. 720 Cell-type resolved spatial proteomics uncovers a novel actionable therapeutic target in toxic epidermal necrolysis. Journal of Investigative Dermatology. 2024;144(8):10.1016/j.jid.2024.06.736

Chiou S, Al-Ani AH, Pan Y, Patel KM, Kong IY, Whitehead LW, Light A, Young SN, Barrios M, Sargeant C, Rajasekhar P, Zhu L, Hempel A, Lin A, Rickard JA, Hall C, Gangatirkar P, Yip RK, Cawthorne W, Jacobsen AV, Horne CR, Martin KR, Ioannidis LJ, Hansen DS, Day J, Wicks IP, Law C, Ritchie ME, Bowden R, Hildebrand JM, O’Reilly LA, Silke J, Giulino-Roth L, Tsui E, Rogers KL, Hawkins ED, Christensen B, Murphy JM, Samson AL. An immunohistochemical atlas of necroptotic pathway expression. EMBO Molecular Medicine. 2024;16(7):10.1038/s44321-024-00074-6

Meier P, Legrand AJ, Adam D, Silke J. Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity. Nature Reviews Cancer. 2024;24(5):10.1038/s41568-024-00674-x